The present invention relates to novel drug treatments for neuropsychiatric disorders, for example anxiety disorders, psychotic disorders, mood disorders and somatoform disorders. These treatments relieve symptoms of disorders characterized by repetitive, stereotyped, an unwanted, intrusive, or involuntary thoughts, perceptions, or behaviors. These include posttraumatic stress disorder, obsessive-compulsive disorder, somatization disorder, hypochondriasis, and body dysmorphic disorder. Contemporary drug therapy for these conditions is limited in efficacy, with many patients continuing to have symptoms despite treatment. Antidepressants, mood stabilizers, anti-anxiety drugs, and antipsychotic drugs all have been used to treat them. Even when they provide some relief, persistent intrusive, repetitive mental phenomena may remain as a distressing symptom. Thus, when a person with posttraumatic stress disorder is treated with an antidepressant, mood may improve while xe2x80x9cflashbacksxe2x80x9d of the traumatic event continue.
Clearly, there is a need for additional medications efficacious for the treatment of these disorders, and especially for medications that suppress or eliminate the recurrent unwanted, intrusive, or involuntary thoughts, perceptions and behaviors characteristic of those disorders. Such medications might also be used to reduce such symptoms when they occur as part of another psychiatric syndrome, such as depression or schizophrenia, or when they are incidental to a neurological disorder such as Tourette""s syndrome or Huntington""s disease.
I begin by reviewing the prototypical conditions for which the novel treatment is useful:
Description of PTSD
Posttraumatic stress disorder is an immediate or delayed response to a catastrophic event, characterized by the following features:
xe2x80x9cre-experiencing the trauma, psychic numbing or avoidance of stimuli associated with the trauma, and increased arousal. Re-experiencing phenomena include intrusive memories, flashbacks, nightmares, and psychological or physiological distress in response to trauma reminders. Intrusive memories are spontaneous, unwanted, distressing recollections of the traumatic event. Repeated nightmares contain themes of the trauma or a highly accurate and detailed re-creation of the actual event(s). Flashbacks are dissociative states in which components of the event are relived, and the person feels as if he or she is experiencing the event for a few seconds for as long as days. Reactivity to trauma-related stimuli can involve intense emotional distress or physical symptoms similar to those of a panic attack, when the patient is exposed to sights, sounds, smells or events that were present during the traumatic event. Avoidance may include thoughts, feelings, situations or activities that are reminders of the trauma. Numbing may occur through amnesia, emotional detachment, restricted affect, or loss of interest in activities. Increased arousal may include insomnia, irritability, hypervigilance, increased startle response, or impaired concentration. This disorder can have pervasive effects on an individual""s interpersonal behavior and all spheres of his or her life.xe2x80x9d (Charney D S et al.: Neurobiological mechanisms of human anxiety. In Fogel B S, Schiffer R B, Rao S M: Neuropsychiatry. Baltimore: Williams and Wilkins, 1996, pp. 257-286).
Epidemiology of PTSD
Among American veterans of the Vietnam War, the lifetime prevalence rate of PTSD was estimated as 31% in men and 27% in women; current prevalence estimates were 15% and 8.5%, respectively. In a survey of female victims of crime, the lifetime prevalence of PTSD was 13% and the current prevalence 3%. Overall, PTSD affects 2% or more of the US population (Charney et al., supra). Among people with work-related injuries, the rate of PTSD may exceed one-third, or even one-half, if people with partial PTSD syndromes are included (Asmundson G J, et al.: Posttraumatic stress disorder and work-related injury. J Anxiety Disord, 12:57-69, January-February 1998). Manifestly, PTSD is a significant public health problem.
Complications and comorbidity
There is a strong association between PTSD and substance abuse, especially alcoholism. (Coffey S F, et al.: Screening for PTSD in a substance abuse sample: psychometric properties of a modified version of the PTSD Symptom Scale Self-Report. J Trauma Stress, 11:393-9, April 1998). In addition, chronic PTSD can increase a person""s long-term risk of a broad range of chronic diseases. Long-term follow up of men exposed to severe combat-related stress showed that PTSD significantly increased the risk of developing disorders of the circulatory, digestive, and respiratory systems as well as, infectious diseases, and neurological and psychiatric disorders other than PTSD (Boscarino J A: Diseases among men 20 years after exposure to severe stress: implications for clinical research and medical care. Psychosom. Med., 59:605-14, November-December 1997).
Various studies over the past decade have identified risk factors for the development of PTSD following an acute traumatic event. These include lower intelligence, a less developed narrative of the traumatic event, a history of prior trauma, and a rapid heart rate at the time of post-trauma medical examination. If a person develops an acute stress disorder after a major traumatic event (i.e., immediately displays symptoms resembling those of PTSD), that individual is likely to continue having symptoms, and eventually warrant, a diagnosis of PTSD. These considerations imply that a population at high risk for PTSD can be identified. If there were a non-toxic drug that significantly and specifically reduced the symptoms of PTSD, it could be used in this high-risk population to prevent the development of PTSD.
Pathophysiology of PTSD
The pathophysiology of PTSD involves disturbances in brain systems involved with reaction to stress, including the hypothalamic-pituitary-adrenal axis, and systems involving norepinephrine, serotonin, endogenous opiates, and endogenous ligands for benzodiazepine receptors. PTSD involves overactivity of the noradrenergic arousal systems, with relative underactivity of the hypothalamic-pituitary-adrenal axis (Henry J P: Psychological and physiological responses to stress: the right hemisphere and the hypothalamo-pituitary-adrenal axis, an inquiry into problems of human bonding. Acta Physiol Scand Suppl, 640:10-25, 1997). On the other hand, underactivity of endogenous opiate mechanisms may contribute to the symptoms of PTSD. (Baker D G, et al.: Cerebrospinal fluid and plasma beta-endorphin in combat veterans with post-traumatic stress disorder. Psychoneuroendocrinology, 22:517-29, October 1997)
Animal experiments suggest NMDA receptor-mediated processes are likely to be involved in the establishment of anxiety-like behavior following stressful events. The latter induce longterm potentiation (LTP) affecting connections within the amygdala, and between the amygdala and its efferents. A natural inference is that NMDA-receptor mediated processes are involved in the development of PTSD in humans (Adamec R: Transmitter systems involved in neural plasticity underlying increased anxiety and defense: implications for understanding anxiety following traumatic stress. Neuroscience and biobehavioral reviews 21(6): 755-65, 1997). In a recent review, two Israeli investigators described a central role of NMDA receptors in posttraumatic stress disorder, as well as schizophrenia, alcoholism and major depression. They proposed that agents that modulate NMDA receptor function would be useful in treating all of these disorders (Heresco-Levy U, Javitt DC: The role of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes. Eur Neuropsychopharmacol 1998 May;8(2):141-52). They did not, however, propose acamprosate in the treatment of PTSD, nor the combination of NMDA receptor and GABA-A receptor actions in the treatment of these disorders.
In addition to the amygdala and its connections, PTSD involves dysfunction of the caudate nuclei. Lucey et al. (1997) in a SPECT study, showed that PTSD symptoms were negatively correlated with caudate blood flow, with the correlation stronger on the right side. (Lucey J V, et al.: Brain blood flow in anxiety disorders. OCD, panic disorder with agoraphobia, and post-traumatic stress disorder on 99mTcHMPAO single photon emission tomography (SPET). Br J Psychiatry, 171:346-50, October 1997).
The role of GABA in the pathophysiology of PTSD has not been settled. Benzodiazepines may relieve anxiety associated with PTSD. However, they usually do not do much for the specific symptoms of the disorder. In a study of trauma survivors, early administration of high-potency benzodiazepines following the trauma did not prevent the development of PTSD, even though it did reduce physiological arousal, e.g. resting heart rate (Gelpin E, et al.: Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry, 57:390-4, September 1996). Moreover, the benzodiazepine antagonist flumazenil did not produce an increase in anxiety of PTSD symptoms in patients with PTSD (Randall PK, et al.: Effects of the benzodiazepine antagonist flumazenil in PTSD. Biol Psych 38(5):319-24, 1995).
Drug treatment of PTSD
Drug treatment of PTSD has had limited success. Not surprisingly in view of this, a wide range of medications have been tried. Individual patients have benefited from various drugs, but none have emerged as a standard treatment. Perhaps the most predictable benefits come from treating manifest anxiety and depression with anti-anxiety and antidepressant drugs, and from treating psychotic symptoms with antipsychotic drugs. These treatments relieve suffering and can improve function, but do not in general alter the core symptoms of intrusive thoughts and images, hyperarousal, and emotional numbing.
Classes of medications that have helped individual patients with PTSD include benzodiazepines, dopamine antagonists (neuroleptics), specific serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, antiepileptic drugs (AEDs), lithium, beta-adrenergic blockers, and clonidine (an alpha 2-adrenergic agonist), to name a few. Cyproheptadine, a serotonin receptor blocker, has shown efficacy for suppression of nightmares in patients with PTSD (Gupta S, et al,: Efficacy of cyproheptadine for nightmares associated with posttraumatic stress disorder. Compr Psychiatry, 39:160-4, May-June 1998). Recently, risperidone, an atypical neuroleptic, was shown to suppress intrusive mental phenomena in children and adolescents with PTSDxe2x80x94though it did not do so completely (Horrigan J, presentation at the American Academy of Child and Adolescent Psychiatry annual meeting, October 1998; reported in Psychiatric News, Dec. 18, 1998.)
A full-text patent search on xe2x80x9ctreatmentxe2x80x9d and xe2x80x9cposttraumatic stress disorderxe2x80x9d yielded 13 relevant patents (U.S. Pat. Nos. 5,028,612; 4,962,128; 5,484,794; 5,488,056; 5,574,028; 5,574,029; 5,574,053; 5,708,014; 5,726,193; 5,763,457; 5,776,969; 5,852,036; 5,852,037), none of which dealt with glutamate or GABA-related mechanisms. Several patents on chemicals affecting NMDA-glutamate neurotransmission include PTSD in a long list of psychiatric disorders potentially treatable with those chemicals. To date, however, no specific glutamate antagonist has been tested as a treatment for PTSD in humans. In particular, there is no literature suggesting or reporting the combination of NMDA receptor antagonists and GABA-A agonists, or the use of a drug with combined NMDA antagonist-GABA-A agonist actions, in the treatment of PTSD.
One recent publication reviews xe2x80x9cThe role of NMDA receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromesxe2x80x9d (Heresco-Levy U, Javitt, D C, European Neuropsychopharmacology 8(1998):L 141-152). The authors note that NMDA antagonists infused into the amygdala can block the acquisition of an enhanced startle response, and infer that glutamate-dependent long-term potentiation may be critical for the development of conditioned fear and encoding of traumatic memories. However, they suggest that enhancers of NMDA receptor-mediated neurotransmission might have therapeutic effects in PTSD. They go on to state that up-regulators of NMDA neurotransmission might also reverse or prevent the cognitive deficits associated with PTSD.
Heresco-Levy and Javitt also describe the hypothesis that schizophrenia is a hypoglutamatergic state, while proposing that excessive NMDA-glutamate neurotransmission may underlie certain cases of major depression. D-cycloserine, a mixed agonist-antagonist binding to the glycine site on the NMDA receptor, is advanced as a treatment for both conditions. It is evident from this and other reviews (not enumerated here) that abnormalities of NMDA-glutamate neurotransmission are associated with psychiatric symptoms and syndromes and the various modulators of NMDA-glutamate neurotransmission are candidates for therapeutic use in mental disorders. However, available literature does not propose that NMDA antagonists would be therapeutic for PTSD, OCD, or the repetitive thoughts, perceptions, and actions that may occur as part of other neuropsychiatric disorders. The literature is totally silent on treatment with agents that combine NMDA antagonism with GABA-A agonism.
In summary, PTSD is a common disorder with significant morbidity and frequent complications, which include physical illness and substance abuse. Available drug treatment is limited in efficacy. Although a role of glutamate and NMDA receptors in the establishment of PTSD is suggested by animal models, specific NMDA receptor antagonists have not been reported as a treatment for PTSD in human patients. There exists the need for additional drugs to treat PTSD, that can provide relief of specific symptoms of the disorder, without unacceptable toxicity. An efficacious drug treatment might not only treat PTSD, but might prevent it if given soon after stress.
Description of OCD
Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by recurrent obsessions or compulsions sufficient to cause marked distress. These behaviors are time-consuming, or significantly interfere with the person""s normal functioning, social activities, or relationships. Obsessions are recurrent ideas, thoughts, images, or impulses that enter the mind and are persistent, intrusive, and unwelcome. Attempts are made to ignore or suppress the thoughts, or to neutralize them with some other thought or action. The individual recognizes them as a product of his or her own mind. Compulsions are repetitive, purposeful behaviors performed in response to an obsession, and are designed to neutralize or prevent discomfort or some dreaded event or situation. However, the activity is excessive, or not connected realistically with that which it is designed to prevent. The affected person recognizes that his or her behavior is unreasonable. (Robertson M M, Yakely J: Gilles de la Tourette syndrome and obsessive-compulsive disorder. In: Fogel B S, Schiffer R B, Rao S M: Neuropsychiatry. Baltimore: Williams and Wilkins, 1996, pp.827-870).
Epidemiology of OCD
Estimates of the lifetime prevalence of OCD in the US have ranged from 1.9% to 3.2%. Milder forms of obsessive-compulsive behavior are even more common. The lifetime risk of developing OCD within a normal life span has been estimated at 5.4% (Bland R C, Newman S C, Orn H: Epidemiology of psychiatric disorders in Edmonton. Acta Psychiatr Scand 77 (Suppl): 338, 1988). The disorder usually is chronic, with only about ⅓ of patients having spontaneous remissions (Robertson and Yakely, supra).
Pathophysiology of OCD
OCD is currently thought to be due to excessive activity in neural circuits involving the orbital frontal cortex, the anterior cingulate region, the caudate nucleus and the thalamus. Recurrent activity in these circuits produces the characteristic recurrent, stereotypic obsessions and compulsions. This localization of OCD has been supported by a number of brain imaging studies with differing methodologies and overlapping results (Saxena et al.: Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry Suppl 1998;(35):26-37). Saxena and colleagues hypothesize hyperactivity of an orbital frontal-subcortical circuit, due to an imbalance of tone in direct versus indirect striato-pallidal pathways. Neuropsychological testing also suggests dysfunction of orbital frontal structures and their subcortical connections (Schmidtke K, et al.: Cognitive frontal lobe dysfunction in obsessive-compulsive disorder. Biol Psychiatry, 43:666-73, May 1, 1998; Purcell R, et al.:
Cognitive deficits in obsessive-compulsive disorder on tests of frontal-striatal function. Biol Psychiatry, 43:348-57, Mar. 1, 1998).
From the standpoint of neurotransmitter function, the broadest scientific consensus supports a role for serotonergic system dysfunction in OCD. (Robertson and Yakely, supra.) Of greatest importance is the observation that serotonin reuptake inhibitors (SRIs) are the most consistently effective drug treatments of the disorder. In addition, studies have shown differences in serotonergic transmission between OCD patients and controls. As one example of many, patients with OCD have a lesser increase in prolactin after d-fenfluramine challenge than do normal controls. (D-fenfluramine is a SRI). Furthermore, patients with more blunting of the prolactin response tend to have worse symptoms of OCD (Monteleone, et al.: Prolactin response to d-fenfluramine in obsessive-compulsive patients, and outcome of fluvoxamine treatment. Br J Psychiatry 170:554-7, June 1997).
Dopamine may also have a role in producing the symptoms of OCD. Direct and indirect dopamine agonists, including levodopa and amphetamine, can produce stereotypical xe2x80x98ritual-likexe2x80x99 behavior in animals, and the use of stimulants in humans has been documented to produce repetitive actions resembling the compulsive behaviors of OCD (Robertson and Yakely, supra). The ability of dopamine antagonists to augment the therapeutic effects of SRIs is compatible with a hypothesis of dopaminergic hyperactivity at synapses involved in symptom production.
More recent research has suggested a role for glutamate in the production of OCD symptoms, and perhaps an ancillary role for a deficiency of GABA. Moore et al. (J. Am Acad. Child Adolesc. Psychiatry, June, 1998 37 (6):663-667) report a case of a 9-year old boy with OCD studied by PET scanning before and after successful treatment with paroxetine, a specific serotonin reuptake inhibitor (SSRI). They found major changes in glutamate resonance in the caudate region. They inferred that serotonin-glutamate interaction was involved in the pathophysiology of OCD. In a study of benzodiazepine receptors in lymphocyte membranes of patients with anxiety disorders, including OCD, patients with OCD had 25% fewer 10 benzodiazepine binding sites than normal controls (Rocca P et al.: Peripheral-type benzodiazepine receptors in anxiety disorders. Acta Psychiatrica Scandinavica 84:6: 537-544, December 1991). This finding suggests that GABA-linked inhibition may be lacking in patients with OCD, as well as in other anxiety disorders.
Drug Treatment of OCD
SRIs (i.e., SSRIs plus clomiprarnine, a tricyclic antidepressant with predominant serotonin reuptake inhibition) are the mainstay of drug treatment for OCD. However, not all patients with OCD respond to SRIs, some do not tolerate them, and many have only a partial response. (Rasmussen S A, Eisen J L: Treatment strategies for chronic and refractory obsessive-compulsive disorder. J Clin Psychiatry, 58 Suppl 13:9-13, 1997). In a 1997 review, Henrietta Leonard notes that xe2x80x9cThe only agents that have shown significant improvement as augmenting agents to an SRI/SSRI in systematic trials have been clonazepam and haloperidol.xe2x80x9d (Leonard H: New developments in the treatment of obsessive-compulsive disorder. J Clin Psychiatry, 58 Suppl 14:39-45; discussion 46-7, 1997). Clonazepam is a GABA-A agonist with effects on serotonergic transmission; haloperidol a dopamine receptor blocker. Other second-line or augmenting agents, for which there is less supporting evidence, include other dopamine antagonists, lithium, clonidine (an alpha 2-adrenergic agonist), monoamine oxidase inhibitors (MAOIs), buspirone (a serotonin 1A agonist), and various other drugs that affect serotonergic transmission. Dopamine antagonists may be more useful in augmenting the response of OCD to SSRIs in patients with a personal or family history of tics (McDougle C J: Update on pharmacologic management of OCD: agents and augmentation. J Clin Psychiatry, 58 Suppl 12:11-7, 1997).
Description of Somatoform Disorders
Somatoform disorders are conditions characterized by physical symptoms without a known physiological explanation, and presumed to be caused by psychological processes. xe2x80x9cThe common feature of the Somatoform Disorders is the presence of physical symptoms that suggest a general medical condition (hence the term somatoform) and are not fully explained by a general medical condition, by the direct effects of a substance, or by another mental disorder (e.g., Panic Disorder).xe2x80x9d (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, D.C., American Psychiatric Association, 1994). Somatoform disorders are divided into a number of syndromes; complete, formal diagnostic criteria for them can be found in the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, supra). Of relevance to this application are three disorders in which repetitive, unwanted stereotyped thoughts, (in this case thoughts about somatic symptoms), are prominent:
1) Somatization Disorder is a chronic condition with onset before age 30 and duration greater than 6 months, characterized by numerous somatic complaints without demonstrable general medical causes, involving several different organ systems, and including four pain symptoms, two gastrointestinal symptoms, one sexual symptom, and one neurological symptom.
2) Conversion Disorder: unexplained sensory or motor complaints without a demonstrable general medical or neurological cause. Complaints are assessed by the clinician as being related to psychological factors.
3) Hypochondriasis is a morbid preoccupation with the fears of having, or the belief that one already has, a serious disease. These are accompanied by misinterpretation of bodily symptoms and evidence from physical examination and laboratory tests that exclude the disease with which the individual is preoccupied. The fears or beliefs cause distress and/or functional impairment, last 6 months or more, and are not relieved by medical evaluation and reassurance.
4) Body Dysmorphic Disorder: is a morbid preoccupation with an imagined defect in appearance, or grossly disproportionate concern about an actual minor physical anomaly. It is often associated with compulsive behaviors such as picking at the skin, reassurance seeking, and mirror checking (Phillips K A: Body dysmorphic disorder: diagnosis and treatment of imagined ugliness. J Clin Psychiatry, 57 Suppl 80:61-4).
Epidemiology of Sornatoform Disorders
Estimates of prevalence vary, depending on the population studied. Obviously, the disorders are much more common in clinical samples than in the general population. However, even in the general population, the prevalence is substantial. A few recent studies illustrate this point.
1) In a community study carried out by general practitioners in two neighborhoods in Florence, Italy, the authors reported the following 1-year prevalence figures: 0.7% for somatization disorder, 0.3% for conversion disorder, 4.5% for hypochondriasis, and 0.7% for body dysmorphic disorder. (Faravelli C, et al.: Epidemiology of somatoform disorders: a community survey in Florence. Soc Psychiatry Psychiatr Epidemiol, 32(1):24-9 January 1997).
2) The prevalence of somatoform disorders in two rural primary care practices was 11.1% (Philbrick J T, et al.: The prevalence of mental disorders in rural office practice. J Gen Intern Med, 1(1):9-15 January 1996).
3) A community survey of Chinese-Americans living in Los Angeles showed a 3.6% prevalence of xe2x80x9cneurastheniaxe2x80x9d, a somatoform disorder not specified in the Diagnostic and Statistical Manual of Mental Disorders, but recognized widely as a discrete syndrome. Neurasthenia has features in common with hypchondriasis and somatization disorder. Of note, these individuals were screened to exclude anxiety disorders or depression as the cause of their somatic symptoms.
Relationship of PTSD to Somatization
Somatoform disorders, like PTSD, involve repetitive unwanted, intrusive or involuntary stereotyped thoughts, perceptions, and behaviors. In addition to this similarity, PTSD, somatization, and dissociation frequently occur together in the same patients. In a study of over 500 individuals who had been exposed to traumatic experiences, PTSD, dissociation, somatization, and affect dysregulation were highly interrelated. (van der Kolk B A, et al.: Dissociation, somatization, and affect dysregulation: the complexity of adaptation of trauma. Am J Psychiatry, 153(7 Suppl):83-93 July 1996). The authors concluded that xe2x80x9cPTSD, dissociation, somatization, and affect dysregulation represent a spectrum of adaptations to trauma. They often occur together, but traumatized individuals may suffer from various combinations of symptoms over time.xe2x80x9d Victims of torture, a most extreme stress, frequently develop a combination of somatization and PTSD (Priebe S; Esmaili S: Long-term mental sequelae of torture in Iranxe2x80x94who 9 seeks treatment? J Nerv Ment Dis, 185(2):74-7 February 1997).
Pathophysiology of Somatoform Disorders
There has been surprisingly little research on the regional brain function in the somatoform disorders in general. However, there has been much work on regional brain function in clinical and experimental pain, using such techniques as PET scanning and functional MRI (FMRI). Similarly, much more is known about the neurochemistry of pain than about the neurochemistry of somatoform disorders. The study of pain is a valuable source of ideas related to the treatment of somatoform disorders, though obviously analgesics are not ipso facto treatments for somatoform disorders, nor would treatments for somatoform disorders necessarily be analgesics. The important link is that emotional distress related to a somatic perception is a common feature of pain and the somatoform disorders mentioned here. The physiological mechanism underlying emotional distress in the somatization disorders is likely to involve limbic system nuclei and pathways related to the emotional (as opposed to the purely sensory) aspects of pain perception. The following section summarizes some facts about pain transmission relevant to the present invention.
GABA, Glutamate, and Pain
Patients with some types of somatoform disorders experience pain. Pain transmission and modulation in the spinal cord are strongly affected by GABA and glutamate. NMDA-receptor mediated processes are involved in the development of states of hypersensitivity to pain. xe2x80x9cInformation concerning amplification systems in the spinal cord, such as the NMDA receptor, is a step toward understanding why and how a painful response is not always matched to the stimulus. Such events have parallels with other plastic events such as long-term potentiation (LTP) in the hippocampusxe2x80x9d (Dickenson A H, et al.: The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord. Gen Pharmacol, 28(5):633-8 May 1997). Ultimately, the balance of NMDA-mediated amplification and GABA-mediated attenuation determines the intensity of the pain signal transmitted from the spinal cord to the brain. Dickenson et al. (supra) observe that in inflammatory conditions, increased GABA activity offsets increased glutamate activity, while in neuropathic pain, it does not. This corresponds to the clinical observation that neuropathic pain may be more excruciating than pain due to tissue damage and inflammation.
Spinal cord stimulation is used clinically to alleviate intractable pain, e.g., from cancer. In animal models, the effect of spinal cord stimulation is to decrease the release of glutamate and aspartate at the dorsal horns, and to increase the release of GABA (Cui J G, et al.: Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism. Pain, 73(1):87-95 October 1997). This supports the idea that more GABA and less glutamate (in the vicinity of NMDA receptors) is associated with analgesia. The spontaneous activity of dorsal horn neurons is suppressed by GABA and increased by glutamate, via an NMDA-receptor dependent mechanism. Augmented release of GABA partially explains the analgesic benefits of transcutaneous electrical nerve stimulation (TENS). In a cat model, the analgesic effects of electrical stimulation of peripheral nerves were partially blocked by picrotoxin, a GABA-A antagonistxe2x80x94suggesting a GABA-A mediated component (Jeong Y, et al.: Effects of iontophoretically applied naloxone, picrotoxin and strychnine on dorsal horn neuron activities treated with high frequency conditioning stimulation in cats. Yonsei Med J, 36(4):336-47 September 1995).
Based on similar studies involving the brain as well as the spinal cord, central pain, due to damage to the brain or spinal cord, has been attributed to a combination of glutamatergic and GABAergic mechanisms.
xe2x80x9cRecent evidence suggests that central pain, i.e., pain due to central nervous system damage, may be due to a deranged neurotransmission between the sensory thalamus and sensory cortical areas. Central pain can be controlled either by opposing glutamate neurotransmission or potentiating GABAergic transmission. It is speculated that a relative hypofunction of the GABAergic inhibition both at thalamic and cortical levels leads to a sectorial excitatory hypertonus in those same areas, A blend of the two should mark, each patient. A pharmacological dissection approach is provided that should optimize the treatment, up to now globally poor, of central pain.xe2x80x9d (Canavero S; Bonicalzi V: The neurochemistry of central pain: evidence from clinical studies, hypothesis and therapeutic implications. Pain, 74(2-3):109-14 February 1998).
Drug Treatment of Somatoform Disorders
Among the somatoform disorders, Body Dysmorphic Disorder has the best established drug treatment, SRIs. (Phillips, supra; Phillips K A, et al.: Efficacy and safety of fluvoxamine in body dysmorphic disorder. J Clin Psychiatry, 59(4):165-71 April 1998; Perugi G, et al.: Fluvoxamine in the treatment of body dysmorphic disorder (dysmorphophobia) Int Clin Psychopharmacol, 11(4):247-54 December 1996). This is perhaps not surprising, in view of its similarity to OCD, which also responds to SRIs in many cases. Phillips points out that augmentation with buspirone or neuroleptics may be helpful in Body Dysmorphic Disorder just as it is in OCD. However, the investigators cited above note that only about ⅔ of the patients they treated improved with SRIs.
For the other somatoform disorders, antidepressants of various kinds are most often used. They often are warranted because the patient has concurrent major depression or dysthymia, but they clearly can work in cases where the somatic symptoms are not accompanied by obvious depression. The concept of xe2x80x9cmasked depressionxe2x80x9d or xe2x80x9cdepressive equivalentxe2x80x9d has been used for decades to explain these responses (Downes-Grainger E, et al.: Clinical factors associated with short-term changes in outcome of patients with somatized mental disorder in primary care. Psychol Med, 28(3):703-11 May 1998.)
When patients"" somatic complaints and concerns reach delusional proportions, they may get relief from neuroleptic drugs. These, of course, have problematic long-term side effects such as tardive dyskinesia.
Some patients may get transient relief of somatic symptoms and concerns from opiates or benzodiazepines. Unfortunately, tolerance develops. Prescription drug dependence or abuse can result.
The use of SRIs for Body Dysmorphic Disorder represents significant progress; so does the awareness that many patients who amplify symptoms will benefit from antidepressant drugs, even if they do not show manifest depression. Nonetheless, not all patients will respond to these treatments. For Somatization Disorder, Conversion Disorder, and Hypochrondriasis, drug treatment to date has been less satisfactory.
The Context of the Invention
In summary, PTSD, OCD and four somatoform disordersxe2x80x94Somatization Disorder, Conversion Disorder, Hypochondriasis, and Body Dysmorphic Disorder, are neuropsychiatric disorders characterized by intrusive, repetitive stereotyped thoughts, perceptions and behaviors that cause significant distress and disability for a substantial portion of the general population. A widely effective and tolerable drug treatment would significantly improve the treatment prospects for patients suffering from these neuropsychiatric disorders. In addition, it would offer a meaningful new treatment option in psychopharmacologyxe2x80x94distinct from antidepressants, anti-anxiety drugs, mood stabilizers (e.g., lithium, valproate), and neuroleptics. Thus, it would offer a new method of treating residual symptoms of patients partially responsive to treatment with any of these established classes of psychotropic agents.